Congenital dislocation of the hip (CHD) is an insidious disease affecting 2-5 of every 1000 newborn children. If uncorrected early, it leads to osteoarthritis of the hip in later life. Identification of the underlying cause of CHD could lead to new approaches to the diagnosis, prophylaxis and therapy of this crippling disease. A very similar heritable hip dysplasia is prevalent in many breeds of dogs, offering a useful animal model in which to test an hypothesis for the cause of CHD: Hip joint laxity is a predysplastic change in genetically predisposed individuals induced by maternally secreted relaxin (Rlx) and estrogens (E2). Maternal E2 and Rlx can enter the fetus, and are also present in colostrum and milk, to be ingested by the nurseling. "Genetic predisposition" could be due either to maternal overproduction or to increased sensitivity of the young to E2 and Rlx. Protecting hips from E2 and Rlx should prevent development of laxity and later dysplasia. Part I will test the above hypothesis, using Labrador Retrievers with an incidence of hip dysplasia of nearly 90% in pups born to dysplastic parents (HD+), but less than 15% in pups born to nondysplastic parents (HD-). Newborn HD+ pups will be treated with the antiestrogen, tamoxifen (T), or a combination of T and antibodies specific for canine Rlx. Antibodies specific for canine Rlx will neutralize the Rlx ingested by the suckling pups, thereby preventing its action on the hip joints. If these treatments reduce hip joint laxity in treated HD+ pups in comparison with untreated HD+ pups, the overall hypothesis will be strongly supported. Newborn HD- pups will be treated with exogenous E2 and cRlx, and their hips evaluated for laxity. Rlx and E2-induced laxity in HD- pups will imply that the genetic defect in HD+ dogs involves maternal secretion of E2 and Rlx; failure of E2 and Rlx to induce hip joint laxity in HD- pups will suggest the genetic defect leading to hip dysplasia is related to an abnormal sensitivity of HD+ pups to Rlx and E2. Part II of the proposal will address the specific mechanisms that could account for the difference in response of the hip joint of HD+ and HD- pups to E2 and Rlx. The levels of Rlx and E2 in cord blood, pup serum and milk and the glandular source(s) of Rlx in HD+ and HD- bitches will be investigated. Rlx-specific mRNA will be isolated from mammary glands, uteri and luteal and noluteal ovarian tissue of HD+ and HD- bitches to detect differences in hormone secretion patterns. Blood levels and metabolism of Rlx and E2 and their receptor patterns in hip joint connective tissue will be compared in HD+ and HD- pups. The possible production of substance that protect hip joints by HD- but not HD+ pups will be addressed. The proposed studies will pinpoint the nature of the genetic defect responsible for predisposition to dysplasia, and suggest new approaches to the treatment of the canine and human diseases.